Fig. 39.17 ). During the digestive phase, intrahepatic TGs accumulate from de novo lipogenesis using the carbons in cytosolic citrate and from endocytosed CRs. Intrahepatic TG, along with other lipids including cholesterol and cholesterol esters, is exported by hepatocytes as VLDL. VLDL particles are assembled as lipids complexed to the ApoB100 protein. Expression of ApoB100, along with other components involved in VLDL assembly, is stimulated by transcription factor FOXO1. FOXO1 in turn is inhibited by the insulin signaling pathway. This means that hepatic VLDL production is minimal during the time when blood is rich in chylomicrons. During the fasting phase, insulin levels are low, so FOXO1 activity is high, and VLDL assembly and secretion resumes. Once VLDL particles enter the circulation, they accept other apoproteins (e.g., ApoE, ApoC2) and become mature VLDL.
Adipocytes display low LPL activity during the fasting phase, in part owing to low insulin levels. However, cardiomyocytes and skeletal myocytes express LPL, which digests VLDL and provides FFA to these muscle cell types during the fasting phase. Lipolytic extraction of some FFAs from VLDL generates a remnant particle called intermediate-density lipoprotein (IDL). IDL circulates to the liver, where it s processed in one of two ways (see
Fig. 39.17 ). About half of the IDL binds to one of several ApoErecognizing receptors, undergoes receptor-mediated endocytosis, and is digested in endolysosomes. Released lipids can be reassembled into VLDL particles and returned to the circulation to provide fuel for cardiac and skeletal muscle as the fasting phase progresses. The other half of the IDL undergoes further digestion from the hepatocyte-specific LPL-related enzyme hepatic lipase. Hepatic lipase extracts most of the remaining TG in the IDL, forming the final remnant of VLDL, LDL. LDL is TG poor but cholesterol rich. It should be noted that both mature chylomicrons and VLDL can receive additional cholesterol from HDL while in the circulation through the action of cholesterol ester transport protein (CETP), so cholesterol content of the remnant particles (ChyR, IDL, and LDL) can vary. In any case the LDL particle is a small, dense, cholesterol-rich particle that is potentially very atherogenic in the face of endothelial damage. LDL particles are safely imported into cells through the LDL receptor. It should be noted that in the conversion of IDL to LDL, the ApoE protein disassociates from the particle. This means that only receptors for which ApoB100 is a ligand can remove LDL from the blood. In contrast to the multiple ApoE receptors, only one receptor, the LDL receptor, can recognize and bind ApoB100. Thus loss or decrease of a functional LDL receptor has significant clinical consequences (see
At the Cellular box). LDL receptor is expressed on proliferating cells, including some cancer cells, which need to synthesize new cell membranes. LDL receptor is also expressed on steroidogenic cells, which use cholesterol to make steroid hormones. The major site of LDL uptake is the liver, which secretes cholesterol as well as cholesterol-based bile acids, as bile into the biliary tree. Some cholesterol is excreted by the intestines. Other cholesterol byproducts (e.g., steroid hormones) are excreted primarily at the kidney.